Repurposing nystatin and taurocholate to target intracellular spore persistence during antibiotic treatment to prevent recurrent Clostridioides difficile infection.
- 1Texas A and M University
Abstract
Successful treatment of primary Clostridioides difficile infection (CDI) while preventing its recurrence remains a major clinical challenge, with recurrent CDI (R-CDI) affecting 20-30% of treated patients. Persistence of C. difficile spores within the intestinal mucosa is thought to drive R-CDI following antibiotic treatment. Here, we show that intracellular C. difficile spores remain protected from taurocholate-triggered germination, and that nystatin, an FDA-approved antifungal that blocks spore entry into host cells, reduces this protected intracellular population and redirects spores toward an extracellular, germinating population accessible to antibiotics. In a murine model of R-CDI, oral co-administration of taurocholate with nystatin and antibiotics during primary CDI reduced R-CDI incidence from 100% to 44%. When administered during an active R-CDI episode, the same formulation reduced a second R-CDI from 100% to 62%. To improve bioavailability, we encapsulated nystatin and vancomycin in chitosan nanoparticles. Oral administration of nanoparticle-encapsulated vancomycin, alone or combined with nanoparticle-encapsulated nystatin, reduced R-CDI colonization to 33% and 44%, respectively, compared with 100% in mice receiving free vancomycin. Together, these findings support a therapeutic strategy that repurposes nystatin and taurocholate, in combination with antibiotics and nanoparticle-based delivery, to target intracellular spore persistence and reduce the incidence of C. difficile recurrence..
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BibTeX
@misc{castrocordova2026repurposing,
title = {{Repurposing nystatin and taurocholate to target intracellular spore persistence during antibiotic treatment to prevent recurrent Clostridioides difficile infection.}},
author = {P. Castro-Cordova and M. Mendoza-Leon and S. Alamos-Musre and J. Munoz-Miralles and F. Diaz-Yanez and F. Marchant-Llancalahuen and D. Cea and R. Hernandez-Armengol and J. Valeria and K. Mondaca and C. Otero and F. Gil and M. Pizarro-Guajardo and D. Paredes-Sabja},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.25.754266},
url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754266v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Repurposing nystatin and taurocholate to target intracellular spore persistence during antibiotic treatment to prevent recurrent Clostridioides difficile infection.
AU - P. Castro-Cordova
AU - M. Mendoza-Leon
AU - S. Alamos-Musre
AU - J. Munoz-Miralles
AU - F. Diaz-Yanez
AU - F. Marchant-Llancalahuen
AU - D. Cea
AU - R. Hernandez-Armengol
AU - J. Valeria
AU - K. Mondaca
AU - C. Otero
AU - F. Gil
AU - M. Pizarro-Guajardo
AU - D. Paredes-Sabja
PY - 2026
DA - 2026/09/25
PB - bioRxiv
DO - 10.64898/2026.09.25.754266
UR - https://www.biorxiv.org/content/10.64898/2026.09.25.754266v1
AB - Successful treatment of primary Clostridioides difficile infection (CDI) while preventing its recurrence remains a major clinical challenge, with recurrent CDI (R-CDI) affecting 20-30% of treated patients. Persistence of C. difficile spores within the intestinal mucosa is thought to drive R-CDI following antibiotic treatment. Here, we show that intracellular C. difficile spores remain protected from taurocholate-triggered germination, and that nystatin, an FDA-approved antifungal that blocks spore entry into host cells, reduces this protected intracellular population and redirects spores toward an extracellular, germinating population accessible to antibiotics. In a murine model of R-CDI, oral co-administration of taurocholate with nystatin and antibiotics during primary CDI reduced R-CDI incidence from 100% to 44%. When administered during an active R-CDI episode, the same formulation reduced a second R-CDI from 100% to 62%. To improve bioavailability, we encapsulated nystatin and vancomycin in chitosan nanoparticles. Oral administration of nanoparticle-encapsulated vancomycin, alone or combined with nanoparticle-encapsulated nystatin, reduced R-CDI colonization to 33% and 44%, respectively, compared with 100% in mice receiving free vancomycin. Together, these findings support a therapeutic strategy that repurposes nystatin and taurocholate, in combination with antibiotics and nanoparticle-based delivery, to target intracellular spore persistence and reduce the incidence of C. difficile recurrence..
ER -